Dysfunction of the serotonin 5-HT1a receptor (5-HT1a) is thought to play a role in the pathogenesis of various disorders such as pain, anxiety and panic disorders, attention deficit and hyperactivity disorder (ADHD) or depression (see e.g. Savitz, Progress in Neurobiology 2009, 88, pages 17-31).
Accordingly, selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, sertraline, paroxetine or citalopram have had significant success in treating depression and related diseases. However, due to their indirect mode of action on the serotonin receptors, SSRIs stimulate serotonergic receptors non-selectively and via a significant delay taking several weeks for the drug to begin reaching its full potential. Also, SSRIs require sufficient endogenous serotonin and in general have been found to be effective in only up to about 50-60% of the patients.
For this reason, directly acting 5-HT1a agonists have been developed.
Buspirone was possibly the 1st direct 5-HT1a agonist, which was approved as a human drug for the treatment of generalized anxiety disorder in the 80th. However, the bioavailability of buspirone is very low; moreover, buspirone is a partial 5-HT1a agonist with remarkable affinity to other receptors such as the dopamine D1 and with an undesirable affinity to adrenergic alpha receptors. There was thus the need for alternative 5-HT1a agonists.
Gepirone and tandospirone are both partial and selective 5-HT1a agonists which share a 4-pyrimidin-2-ylpiperazinylbutyl partial structure with buspirone. While the approval of gepirone for treating anxiety and depression was refused by the American Food and Drug Administration in 2007, tandospirone is only available in China and Japan for treating anxiety and major depressive disorder.
8-Hydroxy DPAT is a compound which is known as full 5-HT1a agonists (Arvidsson et al, J Med Chem 1981, Vol 24.8, p 921; Arvidsson et al, J Med Chem 1984, Vol 27.1, p 45). However, the compound has only been used as a research tool, inter alia because of its very low oral bioavailability (Mason et al, Xenobiotica, 1995, Vol 25.12, p 1371). Also, while 8-OH-DPAT was originally described to have no significant dopaminergic activity it later turned out that the compound also has certain affinity to the D3 receptor (Lejeune, J Pharmacol Exp Ther 1997, Vol 280.3, p 1241).
Various derivatives of 8-OH-DPAT have been published in the 80th and 90th with the aim to improve the pharmacokinetic properties of aminotetralines. These derivatives are mainly based on a modification of the tetraline scaffold such as e.g. annelation to a third ring, leading to orally available benzindol-8-amino derivatives (Hansson, Eur J Med Chem 1997, Vol 32, p 571; Ennis, J Med Chem 1995, Vol 38, p 2217). However, unfortunately this family of benzindoles has been shown to have mutagenic potential by being tested positive in the Ames test (Stjernlöf, J Med Chem 1993, Vol 36, p 2059).
Although various other direct and selective 5-HT1a agonists have been described in literature, none of them have been widely approved for human use up to now. Examples are disclosed in WO 03/106449, WO2009/060030, WO 02/83666, WO 02/60423, WO 04/14915, WO 05/90300, WO 05/12291, or WO 99/65887.
A need therefore exists to provide alternative 5-HT1a agonists.
Preferably, such 5-HT1a agonists are full agonists showing at least about 70%, preferably at least about 80%, more preferably at least about 90%, more preferably at least about 95% activity, even more preferably about 100% agonist activity compared to serotonin in a functional 5-HT1a assay.
In one instance it may be desirable to have partial agonists at the 5-HT1a receptor thus exhibiting between about 30 and about 70% serotonergic activity.
In one instance it is also desirable that such new 5-HT1a ligands are selective 5-HT1a modulators showing significant selectivity to the phylogenetically related dopaminergic and adrenergic receptors. For example, in certain instances it would be advantageous if the new 5-HT1a agonists would have a selectivity to at least one, preferably of two, more preferably of all of D1, D2, D3 and D4 receptors of at least a factor 30, more preferably at least a factor 50, and even more preferably at least a factor of 100, 200 or more.
In contrast, and depending on the disease to be treated it may be advantageous in certain cases if such new 5-HT1a agonists also exhibit significant dopaminergic activity, preferably to the D2 and/or D3 receptor. For example, in the treatment of certain movement disorders related to the dopaminergic system, a 5-HT1a agonists may be desirable that also exhibits D2 and/or D3 affinity thus showing an affinity to the 5-HT1a receptor with a selectivity to D2 and/or D3 of less than about a factor 30, more preferably less then about a factor 20, or 10.
Desirably, the new 5-HT1a agonists are orally available or can be delivered through biological membranes such as the skin or mucosa. For example, it could be of advantage if the new 5-HT1a agonists can be administered transdermally, preferably by passive transdermal systems such as patches.